JPH0193563A - Carboxycyclopropylglycine and production thereof - Google Patents

Abstract

NEW MATERIAL:(2S, 3R, 4S)-alpha-(carboxycyclopropyl)glycine of formula I. USE:The strongest agonist specifically bonding to N-methyl-D-aspartic acid type which is one of receptors of central nervous system of mammal. It provides a clue for developing a blocking agent for glutamic acid receptor. PREPARATION:The objective compound of formula I can be produced by (1) oxidizing a 2-aminobutenol derivative of formula II (R<1> is t-butyldimethylsilyl; Boc is t-butoxycarbonyl) with ozone, (2) reacting the resultant aldehyde with the ylid of bis-2,2,2-trichloroethylphosphorylacetic acid methyl ester to obtain a pentenoic acid ester of formula III, (3) converting the ester into a lactone of formula IV with an acid, (4) reacting with diazomethane to obtain a bicyclolactone of formula V, (5) treating with an alkali and reacting with diazomethane and (6) subjecting the obtained alcohol of formula VI to Jones oxidation, alkali hydrolysis and trifluoroacetic acid treatment.

Description

Detailed Description of the Invention [Industrial Application Field] L-α-(carboxycycloprobyl)glycine has the following formula (1,18,16,1a) 1a
Four stereoisomers are possible, represented by 1b, of which 1G
and 16 have been reported as plant components by L. Fowda% et al., but the stereoisomer 1 has not been reported so far.

The present invention provides (25,3R) represented by formula (1).

4S)-α-(carboxycycloprobyl)chrysin,
The production method, and the batch synthesis method of four types of α-(carboxycycloprobyl)glycine represented by the formulas (1, 18, 1h, la), and (2S.

This invention relates to a simple synthesis method of 35.4R)-α-(carboxycycloprobyl)glycine (16).

L-glutamic acid is considered to be a promising transmitter in the central nervous system, and the present invention (25,3R,4
5) -α-(carboxycycloprobyl)glycine (1
) is one of the receptors in the mammalian central nervous system, N
It exhibits the strongest agonist activity by specifically binding to -methyl-D-aspartate (NMDA) type.

The development of this compound provides a clue to the development of glutamate receptor blockers, and the results may lead to the development of glutamate receptor blockers.
It is expected that it will be used to treat neurological disorders such as Huntinson's disease and Parkinson's disease, as well as neurological mutations.

In addition, the provision of four stereoisomers (1, 1a, 16.1g) provides important knowledge in elucidating the receptor mechanism from the correlation between the conformation and activity of L-glutamic acid and its related compounds. expected to give.

[Prior art and problems to be solved by the invention] L-glutamic acid has been attracting attention as a neurotransmitter in the central nervous system of mammals, and elucidation of its receptor mechanism is one of the most important issues in life science. This is one of the important issues.

1961 FIB g k (L-glutamic acid enhancer using L-glutamic acid related amino acids by %- et al.
agonist) search (D, R, Kurtis (Csrt(a
), J, W, Phillips (P441Hpa), J,
C, r) Tokin x (#7agkisa)% British GA Pharmacology (By4ttak
, /, Pharmaaology), 16.26
2-283, 1961), many substances that exhibit nerve excitatory effects similar to L-glutamic acid have been discovered to date.

In recent years, active research has been conducted on the mechanism of action of these agonists on L-glutamate receptor cells, and it has been shown that L-glutamate receptors can be classified into the following three subtypes (J, C, Watkins (F8 t k t
s a ), R, H, Evasa, Annu Rep Pharmacotetra (A%%%, R-v.

Pharvnaol), Chang, 165-204
, 1981).

1. Receptor cells of each subtype of N-methyl-D-aspartate (NMDAi type 2, kainin WICKAj type 3, and quisqualic acid CQA) are distributed in corresponding specific areas of the central nervous system, and at the same time It has been suggested that it is directly connected to physiological functions [ (=) D, T
-Mona/% y (Mosagha%), V, R, Horetstu (j7o1s*s), D, W, )i (TOW),
C, ii', Cottnas, Nature (Natsbra), 306.176-179.1
983; (h) D, T, Mona/% 7 (, M+s
agAas), D, Yao, C,ll',
: footman (Catsas), plain less (B
rainRam), 1 Yu”, 160-164.1984
; Ce) H+JI orbexwy(□Jwsasgs
), D, T, -E: Nahan CMtssagha*υ,
C, rr, Coinas, J, C, Watkins (iFatki%#), Neil G.A.
t Mac (Esr, J, Phartnac,), 13
1.161-162.1986]. As a result, it is believed that elucidation of the molecular mechanism between agonists and receptors will greatly contribute to the resulting search for antagonists and the development of glutamate receptor blocking systems. In other words, clinical developments in the treatment of epilepsy, movement disorders, neurological disorders such as Huntinson's disease and Parkinson's disease, and neurological mutations are eagerly awaited (B, Meldrum (#s
(drsm), LSI Atlas of Science (A
tlas of Sttm-%6#), 228-232
(1987) Regarding the L-glutamate receptor mechanism Under the above circumstances, the structural relationship between L-glutamate agonists and L-glutamate, which would lead to the development of antagonists, has not yet been elucidated.

The subtype NMDA of the L-glutamate receptor plays an important role in classifying the receptor.

The structural relationship between KA, QA and L-glutamic acid is
It is only assumed that this is due to the conformation of L-glutamic acid (J, C, Watkins, H, T, Olbermann,
1vsha 5as),) Lend In Fist New Oshisu Yayx
(Trend <s Nasroaa4athem
), 10° 265-272, 1987), elucidating the correlation between conformation and activity is an important issue in elucidating the receptor mechanism at the molecular level.

On the other hand, L., Fowdm et al. et al.
L-glycine (1a, 1a) t-isolated, it has been reported that they exhibit effects such as hypoglycemia and emesis (L,
Fotuda Association et al., Phytochemistry (Phytoa
havhimtry), vol. 8, p. 437, 1969). Furthermore, Ofuna et al. started from dt-β-acetoxyglycine and produced trans-carboxycycloglycine (16,16
) reported the synthesis of the racemic form of (Ofuna et al., T.
atrahadro* Lagt, vol. 26, p. 83, 1985). However, the former is only contained in trace amounts in plants, and stereoisomers 1b and 1d are not included. Furthermore, in the latter method, the intermediate [3.3]-sigmatropic rearrangement product is unstable, there is no stereoselectivity in cyclopropanation, and separation between its diastereomers is difficult. In particular, only 1 g of 16Q is given as a racemate. It is a non-natural type (25,3R.

45)-Carboxy, cyclopropylglycide/(1) and its production method have not been known so far, and no method has been reported to date to synthesize four stereoisomers as optically active substances.

[Means to solve the problem]

In connection with L-glutamate receptor mechanism research, the present inventors aimed to clarify the relationship between L-glutamate conformation and activity. , that is, four types of L-α-(
Carboxycycloprovir) Glycun (1* 1 g
+ 1 b * 1 g ), and 1 of them
A novel stereoisomer, (2S.

3R,45)-α-(carboxycycloprobyl)glycine (1) has a strong k
After recognizing that it exhibits i%dimg activity, they developed a stereoselective synthesis method and completed the present invention.

The novel compound (2S, LR, 4S)-α-(carboxycycloprobyl)glycine (1) of the present invention can be produced by the following method.

First, the synthesis of four stereoisomers (1,1g, 16.1g) is carried out using the following formula (7):
R1 represents a hydrogen atom, R1 represents a hydrogen atom or a butyldimethylsilyl group, or a group in which R2 and R1 combine with each other to form a dimethylmethylene group.

The same applies to the following formulas) A (2S)-2-amitubutenol derivative represented by the formula (2S)-2-amitubutenol is reacted with ethyl diazoacetate in the presence of a palladium salt, preferably palladium acetate (1) to obtain the general formula (8). 4 of the carboxycycloprobylglucinol visiting conductor represented by
It is a mixture of stereoisomers of f11.

This mixture was treated with acid or (%-B m
6) (9a) The carboxycyclopropane derivative t-separated can be separated. The remaining two isomers cannot be separated, so
When the mixture was heated with DL-shotanowoolO-sulfonic acid and subjected to silica gel column chromatography again, formulas (9a) and (5) (9g) were obtained.
(5) The carboxycyclopropane derivative and lactone represented by the following can be separated. The thus obtained compounds 9at96t9at are each subjected to Jones oxidation using a conventional method, followed by alkaline hydrolysis, and finally treated with trifluoroacetic acid to obtain the target α-(carboxycycloprobyl)glycine la, 16 and IC. be able to.

In addition, by treating the lactone represented by formula 5 with an alkali, a lactone hepta-opened ring is produced, diazomethane! α-(carboxycycloprobyl)glycine represented by formula 1 can be obtained by subjecting it to Jones oxidation, alkaline hydrolysis and trifluorohydroacetic acid treatment in the same manner as described above. Also, (2S, 3R) represented by formula (1).

45)-α-(carboxycycloprobyl)glycine can be stereoselectively synthesized by the following method.

That is, a butynol visiting conductor represented by the formula (2) (wherein, Rt represents a t-butyldimethylsilyl group and B8 represents a t-butoxycarbonyl group. The same group is represented in the following formulas) is reacted. Ozone oxidation at temperatures below 0°C in a solvent that does not participate in the process, such as methanol,
Osinide is reductively decomposed by a conventional method to obtain an aldehyde derivative. Next, bis-2,2゜2-trifluoroethylphosphorylacetic acid methyl ester is reacted with sodium hydride in a solvent such as tetrahydrofuran under an inert gas atmosphere, and the above aldehyde derivative is added to the resulting ylide solution. The reaction produces a pentenoate ester represented by formula (3).

The pentenoic acid ester (3) obtained in this way is easily ring-closed when treated with a solvent that does not participate in the overall reaction, such as methanol and an acid, preferably DL-camphor-10-sulfonic acid, to form the compound represented by formula (4). You can get lactones.

When this lactone (41t) is dissolved in a solvent such as ether and treated with a diazomethane solution, the bicyclolactone represented by formula (5) can be obtained with a stereoselectivity of 85% or more.

This bicyclolactone (5) can be easily converted into the (25,3R,4S)-α-(carboxycycloprobyl)glycine of the present invention in high yield in the same manner as in the synthesis method described above.

On the other hand, stereoisomer 01) can be synthesized more efficiently by the following method. That is, the 2-amitubutenol derivative represented by formula (10) is treated with an acid such as trifluoroacetic acid in a solvent that does not participate in the reaction, preferably methylene chloride, and then the product is treated with a solvent that does not participate in the reaction, preferably in methylene chloride. is treated with Nt-butoxycarbonylglycine hydroxysuccinimide ester in the presence of a base, preferably triethylamine, in a tetrahydrone run. This product is added to an acid, e.g. DL-camphor-1.
When acetonidized with a 0-sulfonic acid catalyst, the formula (11
) can be obtained.

When oxazolidone (11) is reacted with trimethylsilyl triflotetramethanesulfonate and then with sodium nitrite in a solvent that does not participate in the reaction, such as methylene chloride, a diazo compound represented by formula (12) can be obtained.

A diazo compound (12) with a catalyst, preferably palladium acetate (n)? When allowed to act, a cyclopropane derivative represented by formula (13) can be easily obtained.

Compound 13 was converted to di-1 after acid and then alkaline hydrolysis.
- When treated with butyl dicarbonate, a carboxycyclopropane derivative represented by formula (14) can be obtained.

This carboxycyclopropane derivative (14) can also be synthesized by the following alternative method. That is,
A lactam represented by formula (15) (in the formula, R4 represents a t-butyldimethylsilyl group. The same applies hereinafter) is treated with a catalyst, preferably palladium acetate ([1
By reacting a diazomethane solution in the presence of , a bicyclolactam represented by the formula (16) can be obtained.

When this compound 12 is treated with an acid such as hydrochloric acid, hydrolyzed, and treated with di-t-butyl-dicarbonate, the carboxycyclopropane derivative (14) can be obtained.

Compound 14 obtained in this manner is oxidized with Jones reagent and then treated with trifluoroacetic acid in a conventional manner to obtain C2S,35,4R) represented by formula (1c).
-α-(carboxycycloprobyl)glycine can be obtained.

[Effect]

Assuming that the L-glutamate receptor accepts a special conformation of L-glutamate, the attached
ed oonforrnatios) and folded form (
faldad oosfarmattan).

Among the 4ai carboxycycloprobylglycines obtained by the present invention, compounds 1a and 1h simulate the extended form of the former, and 1 and 1c simulate the folded form of the latter, and the difference in configuration at the β position is the receptor This is thought to provide an important key to explaining the three-dimensional elements in the interaction with

For example, African snail (Achatisa fsl)
One of the several types of neurons that have been found to be highly sensitive to β-hydroxy-L-glutamic acid (L-BHGA) is Periodically osc
The sensitive activity against illating sasros (PON) was determined using BIIGA as an indicator for compounds 1.1a and
Comparing b and 1-, EHGA<1>, 1(3),
1 g (30), 16 (-), Ig (0,03),
Met. In addition, the results of the physiological activity test in rat ap4-%algod showed that compound 1a was kainic acid (KA).
In addition, 1 shows an N-methyl-D-aspartic acid (NMDA) type activity enhancing effect, and in particular, its activity is 100 times that of L-glutamic acid, which is the strongest and exceeds that of NMDA.

Hereinafter, the invention will be explained in more detail with reference to Examples.

Example 1゜Step 1 Neal t-butyldimethylsilyl ether (25)-N
-t-butoxycarbonyl-2-amino-3-butynol t-butyldimethylsilyl ether 4.20tC1
163 ml (0.72 mmol) of palladium acetate (It) was dissolved in 501 nt of an ether solution of 4.5 mmol), and an ether solution (300 ml) of 17.1 f (150 mmol) of ethyl diazoacetate was added over 4 hours. Insoluble materials were removed, and the oily substance obtained by concentrating Solution F under reduced pressure was purified by silica gel column chromatography (20% ether/hexane) to obtain the desired product as a mixture of four stereoisomers. Yield: 1.96f (36,1%) Properties: Colorless oil Step 2: Rubonylcycloprobyl) glycitul 9g (2S, 3
S, 4S) 9g (2S, 3S, 4R) silyl ether (8) 1.90 ? (4.9 mmol) was dissolved in 30 wt of ethanol, and DL-camphor-10-
Sulfonic acid 51'Pt was added, and the mixture was stirred at room temperature for 16 hours.

The solvent was distilled off under reduced pressure and the residue was subjected to medium pressure silica gel column chromatography (50% ether/hexane) to obtain (2
S, 3R, 4R) body (9b) 418■, (25, 35,
4R) body (9c) 124#, (2S, 3S, 4.5)
Mixture of body (9a) and C25,3R,4S) body 1561
1I9, a mixture of 342■ was obtained (total yield: 1.049C)
77.7%)]. C25,35゜45) body (9G) and (
2S, 3R, 4S) mixture 4147Q'i was dissolved in methylene chloride, and DL-camphor-10-sulfonic acid 3
(2) was added and stirred for 18 hours. After washing the reaction solution with a saturated aqueous solution of hydrogen carbonate, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to medium pressure silica gel column chromatography (75% ether/hexane). 2S, 3S, 45) body (9G) 230
■, (2,S,37?,4S) lactone body (518
01nGI was isolated.

0 properties; colorless oil o'H-NMR (360MIIs, CDCLs
, δppm); 0.94 (IH, duck), 1.20 (I
H, groove), 1.28 (3#, t, / = 7.5
Hz), 1°45 (9ff, a), 1.55 (IH,
inertia), 1.77 (1j7.), 2.65 (LM, s)
, 3.17 (1[, groove), 3.60-3.80 (2H9
Chinese), 4.13 (2H, dq, J=7.5, 13
E g ), 4.96 (IH, d , /=9Hg)e
slli spec/I/ (y crn-'):
3372.2984, 0 [α), +72.9° (a O
,50,CHCl,)O Properties; Colorless needle crystals (ether-
Recrystallized from hexane) O melting point; 88.0-89.0°C o'H-NMR (360ME g, CDC4δ
ppm); 1.03 (1#, s), 1.17 (I
H,s), 1.25 (3#.

g, J=7Hz), 1.44 (9H, a), 1.57
(2j7° false), 2.74 (if, a), 3.22 (
IH, duck), 3.60-3.77 (2B, s), 4.1
1C2H,dq.

J=7.14Hg), 4.96 (lH, d, J=8H seismic) oIR spectrum (film, cm-'): 346
0゜3028.1712 0〔α)2D'-47,2゜(a O,55, CEC1
,)O properties: colorless needle crystals (recrystallized from ether-hexane) O melting point: 94.0-95.0°C o "II-NJ%iR (360MHz, CDCL,
, δppm); 1.15 (2H9 vortex), 1.27
(3H, t, J=7Ez), 1.53(In2
regret), 1.77 (1, inertia), 3.02 CIH.

68), 3.61 (IH, Kou), 3.65-3.90 (
2H.

duck), 4.15 (2H, dq, J=7, 14Hz
), 4,95(IH,5) oIR spectrum (film, νcIrL') 339
2.2984.1716 0[α] -56,0°(a O,48, CECL,
)O property: Colorless crystals (recrystallized from ether-hexane) O melting point: 152-154°C o'B-NMR (360AiHg, CDCAs,
δppm); 1.30 (IH, s), 1.40 (
IH, m), 1.43 (9#.

a), 1.5s (IH, m), 1.95 (iH, m),
4.1-4.3 (3B, %), 5.00 (IH, 6
m) 01R spectrum (film, α-'); 332
82984.1734.1710 0[α)D-59,4°(a O,46, CHCl,
) Step 3: (25)-#-t-Butoxycarbonyl-ethoxycyclopropylglycinol (1) 200# (0.73 mmol) was dissolved in acetone 10-, and Jones (loss's) reagent was added under ice cooling. The mixture was added and stirred for 3 hours. After further stirring at room temperature for 1.5 hours, Improper Tool was added under water cooling to completely decompose the excess reagent. After adding an aqueous sodium hydrogen carbonate solution and washing with ether to remove unreacted raw materials, the aqueous layer was adjusted to H2 with citric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was dissolved in tetrahydro7ran3-, and the mixture was diluted with 0.5N aqueous sodium hydroxide solution i, sv2 under water cooling.
In addition, the mixture was stirred for 19 hours. The reaction solution was diluted to pE with IN hydrochloric acid.
2 and extracted with saturated brine and ethyl acetate. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and the oily N- was converted to -butoxycarbonyl-α-(carboxycycloprobyl)glycine 152~(80.0%).
) was obtained.

This was dissolved in methylene chloride 2-, trifluoroacetic acid 2- was added under ice-cooling, stirred for 30 minutes, concentrated under reduced pressure, the resulting residue was applied to a Downs 50Fx4 ion exchange resin column, and after washing with water. The ammonium salt of the target product was obtained by elution with IN aqueous ammonia. This was dissolved in water, adjusted to pH 3 with IN hydrochloric acid, and the resulting crystal t-F was collected.
Recrystallization from water gave 75.2 ml of the hydrochloride salt of the title compound as white crystals.

Melting point 255-258℃ o'H-KMR (3604%ufs, DtO, a
pps); 1.15 (IB, inertia), 1.32 (1
#, hang), 1.76 (if.

%), 1.95 (IB, m), 3.40 CIH, d, J
=9, OBg) 0 [α] 25-15.1° (c049.B, 0) Step 3
The title compound 24.111f was obtained (colorless crystals) from 230 d of the compound (9a) in the same manner as in (A).

Melting point 243-247°C (foam decomposition) o ”11- NMR (360) dHs -Dt()
, δp9rn); 1.25(if, ddd
, / =9.1, 5.7, 5.1#g), 1.
34 (1j7, ddd, J=9.1, 9.1,
5. IHg), 1.71 (IH,%), 1.78 (
IH, ddd, J=9.1, 5.1.

4, OHg), 3.23 (LH, d, J=9.8
H error) O [α] ”+ 102.0° (go, 50.#
, 0) (according to the literature [α)”+107° (a2.Hρ)] The above compound (9a) Zo was prepared in the same manner as in step CA).

The title compound 16.1# was obtained from Da (colorless crystals).

Melting point 17B-180°C *”H-NMR (360MHz, D, 0.apps);
1.18 (iH, ddd, /=6,6,5#m
), 1.46 (if.

ddd, J = 8.5, 8.5, 5ffg), 1
．． 68 (IJ, duck), 1.92 (tH, ddd, J
=8.5, 6.6#g), 3.94(IB, d
, / =10#g) 0[α)”+20.7° (a O,46,H,0)
(In the literature [α] 20 + 2 s° (a i −4
0) ] Lactone body (51801) obtained in Step 2 of Example
R9 (0.35 mmol) t-tetrahydrofuran l-
A 0.5N aqueous potassium hydroxide solution was added to the mixture under cooling with water, and the mixture was stirred for 14 hours. The pH was adjusted to 1 with IN hydrochloric acid under water cooling, and the mixture was extracted with ethyl acetate. After swimming and drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was dissolved in methanol, and an ether solution of diazomethane was added to obtain a methyl ester. Following step CA), the title compound 14.4116P was obtained.
? (colorless crystals).

Melting point 178-180°C o'B-NMR (360AfZfs-DtO, a
pps) ; 1.06 (111, ddd * / =
8.5-7-5 Hz), 1.22 (IN.

ddd, / =8.5, 8.5, 5Hz), 1.
61 (Iff.

dddd, J = 9, 8.5, 7.7#g), 1
．． 94 (IH.

ddd, J=8.5, 8.5, 7#g), 3.
89 (1#, d.

/=9Hg) 0[α]”+97.1°(aO,52,H,0)D Example 2° Step 1: (2S)-2-(ff-t-butoxycarbonyl)amino-3-butynol Silyl ether 600~(1,95
The solution was dissolved in 10-methanol and subjected to ozone oxidation at -78°C. 5-dimethyl sulfide was added to the resulting ozone oxidation product solution and reductive decomposition was performed to obtain an aldehyde with double bonds broken. Remove the solvent under reduced pressure, 1
564W by furnace chromatography using 0t of silica gel 1
9 (yield 95%) of aldehyde compound was obtained. This compound was used in the next reaction without further purification. Sodium hydride 111cm (2,77s) in tetrahydrofuran (
10m) Bis-2,2,2 in suspension at θ℃ under nitrogen flow
-) Lifluoroethylphosphorylacetic acid methyl ester 88
A solution of 111I9 (2.77 oL) in tetrahydrofuran (5-) was added dropwise and stirred for 30 minutes. 78% of the reaction solution
Cool to 18-crown-63,65? (13,
85smo4) in THF (ioWlt) followed by aldehyde 564Ni (1,855sot) in THFC
5d') solutions were sequentially added dropwise and stirred for 2 hours. To the reaction mixture was added 100 g of saturated ammonium chloride aqueous solution at -78 DEG C. and the temperature was gradually raised to room temperature, then 50 g of water was added and extracted with ether (3 times). Anhydrous magnesium sulfate (59) was added to the organic layer and dried, the solvent was distilled off under reduced pressure, and then subjected to silica gel column chromatography. (74% yield) of the title compound 1 was obtained.

Properties: Oily substance JR spectrum (fil A, ycrn-'):
3464.3388.2960.2936.1724.
1652α-1 if-NMR (CDC1,,611m): o, os(
3H, a), 0.09 (3j7.s), 0.92 (9#
, a), 1.48 (9#, a), 3.76 (3H, a)
, 3.80 (3f, s) 4.87 (1j7, d
, / = 11.5Hz), 5.20 (IH.

dd, /=8. Q, 11.5Hg) [α]D-
12,4° (a = 1.00, CHCL,) Step 2: C45)-4-(N-butoxycarbonyl)amino-5-butyldimethylsilyloxy-3CI)-pentenoic acid methyl ester (3 ) 330# (0,918%-t) was dissolved in 5 m of methanol and the D of 11011I was dissolved.
L-camphor-10-sulfonic acid was added and stirred for 16 hours. Ethyl acetate and an aqueous sodium bicarbonate solution were added for extraction, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was dissolved in chloroform 5- and further concentrated to obtain colorless crystals of 180~(92.3%) of the title lactone.

Properties: Colorless crystals, melting point 121.5-122.5℃ [α
) ”+62.5” (e 1.01, CEC1
,)1-1-NMR (100MM g, CDCl-
5-δ ppvs): 1.47 (9H, a), 4.2-
4.6 (3H, regret), 4.80 (1j7,6), 6.
70 (IH,d, z=tOHs), 6.86
(IH, dd, 7=5, 10Hz) IR spectrum/I/(J/crrL″″l): 3340.2988.
17z4.1686 Step 3: Unsaturated lactone (4) 1001n9 (0,469% duck
Palladium acetate (n) 1 in an ether solution of t)
16 Da (0,516 m sacrificial oL) was dissolved and added to an ethereal solution of diazomethane on t-TLc until the starting material disappeared. Insoluble matter was removed and the mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (90% ether/
Hexane) to give the title compound 33~(31.1%)
t-threo body (15, 55.

6R): Erimoro body (17?, 5S, 6,5) = 6:1
It was obtained as a mixture of.

The physicochemical properties of the threo form (5) are as follows: Example 1, Step 2
It was completely identical to the lactone obtained in .

Example 3゜Step 1: (25)-(N-fog-butoxycarbonyl)-2-amino-3-butynol (10) 1.38 t (7,
4tnmeL) It was dissolved in t-methylene chloride, 5s6t of trifluoroacetic acid was added under water cooling, and the mixture was stirred for 1 hour.

The reaction mixture was concentrated under reduced pressure, dissolved in 15 ml of tetrahydrofuran, adjusted to pH 8 with triethylamine, and heated with N at -20°C.
2.429 (8.9 mol) of hydroxysuccinimide ester was added to the mixture, and the mixture was stirred for about 3 hours while slowly raising the temperature to room temperature. The mixture was diluted with ethyl acetate and washed sequentially with a 10% aqueous citric acid solution, water, and saturated hydrogen carbonate, an aqueous IJ solution, and water, and the organic layer was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, it was purified using a silica gel column Chromadog 2F (20% methanol/chloroform) to give the title compound 1.48P (yield: 82
．． 0%) t-obtained.

Colorless crystal, groove, j, 76.0-77.5℃ [α) D-3
2,4°(a = 1.01, CHCL, )"H
-NMR (100MEg, C'DCL, , ap
pm): 1.46 (9H, a), 3.76 (1,%)
, 4.56 (I H, m ), 5.24 (2j7,
s), 5.44 (if.

瀉), 5.84 (1j7.ddd, /=6.10.16
1g) 6.70 (IH, d, J=8Hz) JR
Spectrum (να-”): 3312.2984.170
0.1668 Step 2: 1.48f of (2S)-(#-t-butoxycarbonylglycyl)-2-amino-3-butynol obtained in previous step 1
t-acetone 10d, 2,2-dimethoxypropane 10d
DL-camphor-10-sulfonic acid 10
rv' and heated at 80°C for 16 hours. After cooling, the mixture was diluted with ether, washed with a saturated aqueous sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (5% methanol/dichloroform) to obtain the desired product as a 1.14 Pi oil.

Properties: Oily substance [α) D-12.4° (a = 1.05, CHCts
)"11-NMR (100MHz, CDCLB,
a pptn): 1.44 (97/-→, 1.55
(3B, s), 1.67 (3B, a), 3.87 (3H
, 4.14 (2B.

duck), 5.25 (2H, haze), 5.34 (IB, &),
5.84 (IH, ddd, J=7, 9, 16B
g) IR spectrum (ν): 3432.3100
．． 1714.1662 Step 3: Bog-glycine form (11) 9921R9 (3,49
m5et)' was dissolved in methylene chloride, 812 μt (6,98 smot) of 2,6-lutidine, and 1.01 m (5,98 smot) of trimethylsilyl trifluoromethanesulfonate.
235set) f was added and stirred at room temperature. After 15 minutes, methanol was added and the reaction mixture was directly purified by silica gel column chromatography (chloroform to 10% methanol/chloroform).

Dissolve the obtained oil in 5 m of water and add 24 m of sodium nitrite.
089 (3,48smot) f@e, p with citric acid
The mixture was adjusted to H4 and extracted with ether 10-. This operation t-
The ether solution obtained repeatedly five times was dried over magnesium sulfate, and the pore size solvent was distilled off under reduced pressure to obtain the target product 473η as a yellow oil. (Yield 69.5%) Properties: Yellow oil “Ii-NMR (100MHg, CDCL,
δpptyh): 1.60 (3#, a), 1.68 (
3H-→, 3.86 (IB, Tsuru), 4.09 (2B, Regret), 4.84 (IB.

a), 5.26 (2H, s), 5.84 (iB, 5)I
R spectrum (Jiraudou): 2936.2108% Step 42, U Diazo compound (12) 230-(117 capt) was dissolved in toluene 30- and a solution was dissolved in palladium acetate (It).
The mixture was added dropwise into a 13 ml toluene solution at 80° C. over 2 hours. After cooling, toluene was distilled off under reduced pressure and purified by silica gel column chromatography (Nyethyl) to obtain 73.3 das (37.4%) of erythro form (IR, 75,8S),
Threo type (15, 75.

372) 11.6 m9 (5.9%) was obtained.

Properties of erythro form (IR, 7, S, 8S) (13): Amorphous [α] n + 52.06 (a O-53-Maol
l) @H-NMR (10ONB dew, CDC1,, δpp
regret) 20, 98 (IB, 嘱), 1.22 (1, inertia), 1
．． 36 (3#, s), 1.77 (3H, a), 1.94
(2H.

%), 3.39 (lH, dd, J=9.12H dew), 3
．． 98 (2H, s+a) IR spectrum (ν size: 3080.2988, step 5
: (1c) Step 4 acetonide form (13) 60 Da (0.3 setm
mot) It was dissolved in t-60% acetic acid and stirred for 16 hours.

After the acetic acid was distilled off under reduced pressure, it was dissolved in tetrahydrofuran 1-0.
1 di of 5N aqueous sodium hydroxide solution was added, and the mixture was stirred at 70° C. for 4 hours. After neutralizing with IN hydrochloric acid, the pH was adjusted to 9 with an aqueous solution of sodium hydrogen chloride, and di-6-butyl-dicarbonate 1 was added.
25μtc0.544m5*L)'fr was added and stirred for 16 hours. After washing the reaction solution with ether, the aqueous layer was cooled with water.
The pH was adjusted to 2 with hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain alcohol compound 62. (Yield 70.5%) Stirred for 14 hours. After adding isopropyl alcohol to decompose excess reagent, insoluble materials were removed, diluted with Wat-ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance 551119 (84.0%).

This oil was dissolved in 1 ml of methylene chloride, 0.5-trifluoroacetic acid was added thereto, and the mixture was stirred for 30 minutes. The solvent was then distilled off under reduced pressure, leaving a residue of 50 w x 4 (100-2
00 groove ash) was subjected to column chromatography.

After washing with water, the solution was dissolved with IN aqueous ammonia to obtain the ammonium salt of the target product. This was dissolved in 0.5% water and adjusted to pH 3.0 to precipitate crystals.The crystals were recrystallized from the water taken from the tank to obtain 12.5 ml of the desired product as white crystals.

Properties: Colorless crystal [α] ”+20-7@(a O, 46, 40)”E
-NMR (36ONE g, CDCl, , δp
pm>:1.32 (L#, ddd, J = 5, 6
, 6Rg), 1.46 (IH, ddd, /=5,
8.5, 8.511m), 1.68 (IB, inertia),
1.92 (IH, ddd, J=6.6.

8.5j7g) Example 4゜Lactam (15) 2001119 (0,611s@
palladium acetate (■) to 10 ml of ether solution of ot)
(0,031 mm@L) was dissolved and an ethereal solution of diazomethane was added until the starting material disappeared on TLC.

Insoluble material X (I) was removed, and the residue was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (50% ether/hexane) to obtain 242 Da of compound (16) as a t-oil.

Without separating the diastereomers, 20011 g was dissolved in methanol 5-, IN hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, dissolve in ethanol 5-0.5
Add 5 dt of IJ aqueous solution (N hydroxide) and heat at 80°C for 5
heated for an hour. After cooling, ether was added for extraction, and the aqueous layer was neutralized with hydrochloric acid and adjusted to jff 9 with sodium hydrogen carbonate. Dioxane 3- and di-t-butyl dicarbonate (140μ/, (0.61% mol) f) were added and stirred for 16 hours. After washing the reaction solution with ether, the aqueous layer was cooled with ice.
The mixture was adjusted to H2 with N-hydrochloric acid and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure to obtain 82 das of the title compound (14).

This compound (14) could be easily converted to (25,35,4R)-α-(carboxycycloptovir)glycine 0]) in the same manner as in Example 3, Step 5.

Test example R, H, method of Evasa et al. (Evasa R, Ii,
,Wat-ni 4sa,J ,C,Esropaa*
J, Pkarthaa, 50. 1 2 3
-129 (1978)).
d) Using f, depolarization (d) from the ventral root of the motor neuron (M.
S・lari-satims: gga(tag(a)
s) The activity is L-glutamic acid, the compound of the present invention 1.18
．． 16 and 1− concentration i o−s x ~1o−”h
The r rc (low effective concentration CMEC) was measured as an extracellular recording.

〔result〕

The test results are shown in Table-1.

Table-1 1: L-glutamic acid 2: Activity disappears in the presence of Mg++ ions・3
: Unaffected by the presence of MQ” ion 4 to 4:
Glutamate receptors in the mammalian central nervous system are
Three subtypes: 1) NMDA type, 2) KA
Compound 1 of the present invention is classified as type 3) QJ4, but it is thought to act on NMDA type receptors since its activity disappears in the presence of Mg++ ions. As can be seen from Table 1, its activity is 100 times that of L-glutamic acid, and that of N-methyl-D-aspartic acid (activity: 2X10-"), which is considered to be the strongest so far.
), and is expected to be useful as a neurotransmission test drug.

Patent applicant: Suntory Limited (4 others) Procedural amendment 1. Indication of the case 1986 Patent Application No. 129626 2, Title of invention Carboxycyclopropylglycine and its manufacturing method 6,
Relationship with the case of the person making the amendment Address and name of the patent applicant (190) Suntory Ltd. 4, Agent 5, [Claims] and [Detailed Description of the Invention] columns of the specification subject to amendment (1) The scope of claims is amended as follows.

"L (28.!tR,48)-α-(carboxycycloglovir) chrysin represented by formula (1).

2 A 2-amitubutenol derivative represented by formula (2) is oxidized with ozone, and the resulting aldehyde is treated with ylide of bis-2,2゜2-triclotetraethylphosphorylacetic acid methyl ester to form a derivative represented by formula (3). This pentenoic acid ester is then treated with an acid to form a lactone represented by formula (5), which is then reacted with diazomethane to form a bicyclolactone represented by formula (5). The (2S, 3R,
48) Method for producing -α-(carpoxycyctetrapropyl)glycine.

(In each of the above formulas, Boa is a t-butoxycarbonyl group.
R" represents t-butyldimethylsilyl group.) λ -
A carboxycycloprobyl derivative represented by the general formula (8) is obtained by reacting ethyl diazoacetate with 2-amino-3-butynol 11-diyl derivative represented by the formula (7) in the presence of a palladium salt, and this is converted into a carboxycycloprobyl derivative represented by the general formula (8). Or treated with tetra(n-butyl)ammonium fluoride to obtain the following four stereoisomers C96e9be9C,
9d> mixture.

(9α) (9b) The mixture is subjected to silica gel chromatography to separate the stereoisomers of the carpoxycyclopone derivatives represented by formulas (9b) and (9c), and the remaining mixture is converted into DL- After treatment with camphor-10-sulfonic acid, the carboxyschiff-propane derivative of formula (9a) and the lactone derivative of formula (5) were separated by silica gel column chromatography, and the stereoisomer (9α) thus obtained was obtained. , (9A) and (9C) were oxidized with Jones reagent, followed by alkaline hydrolysis and trifluoroacetic acid treatment to produce α-(carboxycycloglobil)glycine represented by the following formulas 1α, 1b and 1c eL1b C , respectively. , and the chtonic body represented by formula 5 is treated with an alkali, then reacted with diazomethane, and then sequentially subjected to Jones oxidation, alkaline hydrolysis, and trifluoroacetic acid treatment. Formula 1g, characterized in that it produces glycine.

1.1? , 1, 411[α-(carboxysifkyopypyl)glycine isomer production method.

(In each of the above formulas, Boc represents a t-butoxycarbonyl group, RR represents a hydrogen atom, R3 represents a hydrogen atom or a t-butyldimethylsilyl group, or R1 and R3 combine with each other to form a dimethylmethylene group. Indicates the group formed.

The same applies hereafter) 4 Formula a [N-
The oxazolidone represented by the formula aυ is obtained by reacting with t-butoxycarbonylglycine hydroxysuccinimide ester, followed by treatment with diacetone dimethyl acetal, acetone and DL-camphor-10-sulfonic acid, and converting this oxazolidone into trifluoromethanesulfonic acid. The diazo compound was treated with trimethylsilyl followed by sodium nitrite to give a diazo compound of formula Q, and this diazo compound was treated with palladium acetate (ID) to give an acetonide of formula (13), which was treated with acid and then with alkali. Then, a compound represented by the formula αXH is obtained by reacting with di-t-butyl dicarbonate, or a lactam represented by the formula (L9 is reacted with diazomethane in the presence of palladium acetate (I)) This lactam was then treated with an acid to remove R4 and Boa groups, and then treated with an alkali to open the lactam ring, and then treated with di-t-butyl-dicarbonate to form a compound represented by the formula I. , this compound <14) is oxidized with Jones reagent and then treated with trifluoroacetic acid to give α-(carboxycycloprobyl)glycine represented by the formula (1C) sweet (28,3S,4R)-α-( Process for producing glycine (carboxycyclopropyl).

(In each of the above formulas, Boa represents a t-butoxycarbonyl group, and R4 represents a t-butyldimethylsilyl group.) (2) The specification is corrected as follows.

Page Line Wrong Correct 11
1 1c) 1c) 161 ND
MA NMDA 16 2 kinding depolarization 21 9 acetonide acetonide 255
Sensation (eyelids open) 62 Lower 3 -15.1° (c O, 49-20,
2°(co, 5134 1 +20.7°(c
O, 46 + 20.8° (c O, 523744, 87
Page 5, 87 Line Wrong Correct 374
5.20 6.20 3810 6.70 6.07 or more

Claims (1)

[Claims] 1. (2S,3R,4S)-α-(carboxycyclopropyl)glycine represented by formula (1) ▲Mathical formula, chemical formula, table, etc.▼(1). 2. Formula (2) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (2) Ozone oxidation of the 2-aminobutenol derivative represented by the formula (2) results in aldehyde produced with methyl bis-2,2,2-trichloroethylphosphorylacetate. By reacting the ylide of the ester, a pentenoic acid ester represented by the formula (3) ▲There are mathematical formulas, chemical formulas, tables, etc. There are mathematical formulas, chemical formulas, tables, etc. ▼ (4) After making the lactone represented by , diazomethane is reacted to form the bicyclolactone represented by formula (5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5) This is treated with an alkali and treated with diazomethane to produce an alcohol represented by the formula (6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (6) This alcohol is then subjected to Jones oxidation, followed by alkaline hydrolysis and trifluoroacetic acid treatment. (2S
, 3R, 4S)-α-(carboxycyclopropyl)glycine. (In each of the above formulas, Boc represents a t-butoxycarbonyl group,
R^1 represents a t-butyldimethylsilyl group. ) 3, General formula (7) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (7) The general formula (8 ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) A carboxycyclopropyl derivative represented by (8) is treated with an acid or tetra(n-butyl)ammonium fluoride to form the following four stereoisomers (9a, 9b, 9c,
9d) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9c) ▲ Mathematical formulas, chemical formulas, There are tables etc. ▼ (9d) The mixture was subjected to silica gel chromatography and the formula (
The stereoisomers of the carboxycyclopropane derivatives represented by 9b) and (9c) are separated, and the remaining mixture is DL-
After treatment with 10-sulfonic acid, it was subjected to silica gel column chromatography to separate the carboxycyclopropane derivative of formula (9a) and the lactone derivative of formula (5). Stereoisomers (9a), (9b) thus obtained
By oxidizing and (9c) with Jones reagent, followed by alkali hydrolysis and trifluoroacetic acid treatment, the following formulas 1a, 1b and 1c are obtained, respectively. 1b ▲There are mathematical formulas, chemical formulas, tables, etc.▼1c α-(carboxycyclopropyl)glycine represented by is produced, and the lactone body represented by formula 5 is treated with alkali and then reacted with diazomethane, followed by Jones oxidation and alkali Formula 1a, 1b, 1c, which is characterized by producing α-(carboxycyclopropyl)glycine represented by Formula 1 by hydrolysis and trifluoroacetic acid treatment.
1. Method for producing four types of α-(carboxycyclopropyl)glycine isomers. (In each of the above formulas, Boc represents a t-butoxycarbonyl group, R^2 represents a hydrogen atom, and R^3 represents a hydrogen atom or a t-
Butyldimethylsilyl group or R^2 and R
^3 represents a group that combines with each other to form a dimethylmethylene group. (The same applies hereafter) 4. Formula (10) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (10) N- to the 2-amino-3-butenol derivative represented by
By reacting with t-butoxycarbonylglycine hydroxysuccinimide ester and subsequently treating with acetone dimethyl acetal, acetone and DL-synthetic-10-sulfonic acid, the formula (11) is obtained.▲Mathematical formulas, chemical formulas, tables, etc.▼(11) This oxazolidone is treated with trimethylsilyl trifluoromethanesulfonate and then with sodium nitrite to form a diazo compound of formula (12) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (12) is treated with palladium(II) acetate to obtain acetonide represented by formula (13) ▲Mathematical formula, chemical formula, table, etc.▼(13) After treatment with acid and then alkali, di-t-butyl dicarbonate is obtained. to form a compound represented by formula (14) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (14) or formula (15) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (15) The lactam is treated with diazomethane in the presence of palladium (II) acetate to form a bicyclolactam represented by the formula (16) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (16), and this lactam is then treated with acid to form R^4 After removing the Boc group and opening the lactam by alkali treatment, di-t-butyl-
A compound represented by the above formula (14) is obtained by the action of dicarbonate, and this compound (14) is oxidized with Jones reagent, and then treated with trifluoroacetic acid to form the formula (1c) ▲ Numerical formula, chemical formula, table, etc. ▼ ( 1c) A method for producing (2S,3S,4R)-α-(carboxycyclopropyl)glycine, which is α-(carboxycyclopropyl)glycine represented by: (In each of the above formulas, Boc represents a t-butoxycarbonyl group, and R^4 represents a t-butyldimethylsilyl group.)